Spring Assisted Drug Delivery Device

ABSTRACT

A spring assisted drug delivery device comprising: a housing; a piston rod having a longitudinal axis, a distal end and a proximal end that is axially movable in a distal direction relative to the housing, a mid-body fixed inside of the housing and coupled to the piston rod in such a manner that the piston rod is axially movable in a distal direction relative to the mid-body, and wherein a preloaded spring is operatively coupled to the piston rod in such a manner that the spring is released and the stored force in the spring supports driving the piston rod in the distal direction during a dose administration step.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a U.S. National Phase Application pursuant to35 U.S.C. §371 of International Application No. PCT/EP2014/074703 filedNov. 17, 2014, which claims priority to U.S. Provisional PatentApplication No. 61/907,569 filed Nov. 22, 2013 and European PatentApplication No. 14165747.8 filed Apr. 24, 2014. The entire disclosurecontents of these applications are herewith incorporated by referenceinto the present application.

FIELD OF INVENTION

The present patent application is generally directed to pen-typeinjection devices and specifically the dose setting mechanisms for suchdrug delivery devices. Such devices provide for self-administration ofmedicinal product from a multi-dose cartridge and permit a user to setthe delivery dose. The present application may find application in bothdisposable and reusable type drug delivery devices. However, aspects ofthe invention may be equally applicable in other scenarios as well.

BACKGROUND

Pen type drug delivery devices have application where regular injectionby persons without formal medical training occurs. This is increasinglycommon among patients having diabetes where self-treatment enables suchpatients to conduct effective management of their disease. Diabetes hasbeen shown to cause certain problems. For example, people with diabetescan get high blood pressure, kidney disease, nerve damage, heartdisease, and even in certain circumstances blindness. The damage causedby these problems may occur in patients whose blood sugar has been outof control for years. Keeping blood sugar under control, by way ofeffective insulin administration, is one method that can help preventthis damage from occurring.

In addition, people with diabetes can go into “diabetic coma” if theirblood sugar is too high. They can also develop blood sugar that is toolow (i.e., hypoglycemia) if they don't get enough food, or they exercisetoo much without adjusting insulin or food. Both diabetic coma andhypoglycemia can be very serious, and even fatal, if not treatedquickly. Closely watching blood sugar, being aware of the early signsand symptoms of blood sugar that is too high or too low, and treatingthose conditions early can prevent these problems from becoming tooserious.

Pen type drug delivery devices have been designed and developed to helppatients suffering from diabetes and other disease states so as toprevent such problems from occurring. The circumstances identified abovehighlight a number of design considerations and criteria for drugdelivery devices, especially those that may be used to treat diabetes.As just one example, one requirement is that the drug delivery devicemust be robust in construction. The drug delivery device must also beeasy to use both in terms of the drug delivery device manipulation andunderstanding of the device's operation. Diabetics, for instance, haveto inject themselves repeatedly with insulin solution and the volume ofinsulin to be injected may vary from patient to patient and even frominjection to injection. For at least this reason, certain diabetics mayrequire drug delivery devices that allow the patient to injectsuccessive measured dosages of the same or perhaps different presetvolumes of insulin solution accurately and with minimum dexteritychallenges. This presents a further design challenge since, in the caseof certain diabetics, users may have impaired vision and/or may bephysically infirm with limited dexterity.

Generally, pen type injection devices include a cartridge having aslidable piston and containing a multi-dose quantity of liquidmedication. A lead screw extending from the dose setting mechanism ofthe injector pen is movable in a forward (i.e., distal direction) toadvance the piston within the cartridge in such a manner as to dispensethe contained medication from an outlet at the opposite cartridge end,typically through a needle that penetrates a stopper or septum at thatopposite end. In disposable or prefilled pens where the cartridge ispermanently sealed within the pen housing, after a pen has been utilizedto exhaust the supply of medication within the cartridge, the entire penis then discarded. In reusable pens, after a pen has been utilized toexhaust the supply of medication within the cartridge, the pen isdisassembled to allow replacement of the spent cartridge with a freshcartridge, and then the pen is reassembled for its subsequent use.

A number of pen type injection devices are commercially available andunfortunately a number of those devices suffer from one or more designflaws that may result in the improper use of the injection device or thedelivery of an inaccurate dosing of the medicament. Inaccurate dosesetting could lead to fatal results. Other design flaws allow thepossibility that a counterfeiter can dissemble a disposable pen andinsert bogus medicament cartridge. This pen is then reassembled and soldas new. Such design flaws may not be realized when a pen is firstcommercialized and may only become apparent after the injection devicehas been in commercial use by patients for an extended period of time.As such, there exists a need to evaluate existing pen designs toidentify the design flaws and then take corrective action, whichtypically would include redesigning certain original mechanisms withinthe injection device.

One such pen injector lending itself to design improvements is describedin WO 2005/0188721. The following describes a number of such designflaws and presents corrective solutions to eliminate these flaws.

SUMMARY

In most, if not all, pen injection type devices dose accuracy issignificantly affected if the distal end of the lead screw, through theassociated bearing, is not in continuous engagement with the proximalend or face of the cartridge piston prior to the user setting a dose.Stated another way, in some dosing mechanism designs there is one ormore flaws that allows the lead screw to move or otherwise translate offthe piston proximally after a dose is injected and before a subsequentdose is set. In these cases the bearing is no longer in contact with theproximal end of the piston thus creating a gap or void space between thedistal face of the bearing and the proximal face of the piston. When anext dose is set and delivered, the lead screw would necessarilytraverse this unintended gap before contacting and moving the piston.Because there is no movement of the piston during this gap closure, andhence no expulsion of medicament from the cartridge, the actual dosedelivered will be less than that set by an amount directly proportionalto the size of the gap. Accordingly, it is of prime importance toprevent any unintended proximal movement of the lead screw between dosedelivery and the setting of the next dose. Stated differently, thedosing mechanism must include structures to prevent any proximalmovement of the lead screw relative to the cartridge piston.

A physical examination of the commercial pen injection device that isgenerally described in WO 2005/018721 shows that if a user pushes thedose knob in the distal direction and simultaneously rotates the doseknob in either direction (clockwise or counter clockwise) the lead screwis advanced in either the proximal and distal directions.

Another perceived problem of this commercial injection device is that itis entirely a manual activated pen device. That is, this commercialmedication delivery pen may be termed a manual pen since the injectionof a medicament contained within the pen is delivered by a force that ispurely provided by the user of the pen. As such, the injection of amedicament is not assisted by any type of mechanism, such as a springelement. One disadvantage of such a purely manually driven pen is thatthe user will be called upon to apply a force to withdraw the dosesetting member a certain axially fixed distance and then press upon thedose setting member to perform the injection. This may be a difficultmanual procedure, especially for persons having reduced motor skills orreduced finger strength, such as a child, elderly people, disabledpeople; or those suffering from diabetes. To solve this problem, thepresent invention modifies the original design of dosing mechanism so asto provide a spring assisted feature during a dose administration step.

The disclosure concerns a method and system for proving a springassisted drug delivery. A spring assisted drug delivery device maycomprise a housing and a lead screw having a longitudinal axis, a distalend and a proximal end that is rotatably fixed during dose setting anddose delivery and axially movable in a distal direction relative to thehousing. The lead screw may include a threaded shaft and a bearing footconnected to the distal end, wherein the lead screw has a smooth keywaypositioned parallel to the longitudinal axis. A cartridge with a movablepiston at one end and an outlet at the other end may be provided. Thepiston is engageable by the lead screw bearing to be advanced towardsaid outlet when the lead screw is moved distally. A drive nut isthreadedly engaged and screwable along the lead screw threaded shaft. Anumber sleeve is threadedly engaged with the housing to be screwablerelative to the housing. A mid-body is axially fixed inside of thehousing, the mid-body comprising tabs that slidably fit within thekeyway in the lead screw to prevent rotation of the lead screw withinthe housing. A preloaded spring is provided that assists a user of thedevice during a dose administration step.

The key idea is providing a spring assisted drug delivery devicecomprising a housing, a piston rod having a longitudinal axis, a distalend and a proximal end that is axially movable in a distal directionrelative to the housing. The drug delivery device further comprises amid-body fixed inside of the housing and coupled to the piston rod insuch a manner that the piston rod is axially movable in a distaldirection relative to the mid-body. A preloaded spring is operativelycoupled to the piston rod in such a manner that the spring is releasedand the stored force in the spring supports driving the piston rod in adistal direction during a dose administration step.

The mid-body and the housing may be integrally formed or being separatecomponents having been connected. The connection may be permanent orreleasable. The mid-body is at least axially fixed inside the housing.

Since the invention is not limited to a lead screw which may serve fortransferring turning motion to linear motion, the term “piston rod” hasbeen used. The term “piston rod” shall preferably mean a componentadapted to operate through/within a housing of the delivery device,which may be designed to move axially through/within the deliverydevice, for example for the purpose of discharging or dispensing aninjectable product. “Piston rod” shall further mean a component having acircular or non-circular cross-section. It may be made of any suitablematerial known by a person skilled in the art and may be of unitary ormultipart construction. One embodiment of a piston rod may be a leadscrew that has a thread.

Operatively coupled components may be coupled directly, e.g. beingconnected or engaged, or indirectly, i.e. by means of other components.The components may be connected in a form-fit, force-fit, or materiallybonded manner. Alternatively, the components may merely touch each otheror abut each other in such a manner that a force or movement may betransferred. Components that are coupled may or may not be able to move,e.g. axially and/or rotationally, with respect to each other.

In one embodiment, the preloaded spring is operatively coupled betweenthe mid-body and the piston rod or between the housing and the pistonrod. The preloaded spring may be operatively coupled between themid-body and a bearing of the piston rod. In one embodiment, thepreloaded spring is operatively coupled to a separate bearing surfacecomponent affixed to a proximal surface of the bearing. The preloadedspring may comprise a wave spring which may be operatively coupled to aproximal surface of the bearing. The piston rod may be embodied as alead screw which includes a threaded shaft and a bearing connected tothe distal end.

For example, in one arrangement, a modification is made to the mid-bodyand lead screw bearing of the pen type delivery device so as toaccommodate a spring. Such a spring may be a compression spring or awave spring or other similar biasing element. In this arrangement, asthe device is provided to the user, the spring is preferably provided ina preloaded or a pre-stressed state. This pre-loaded spring defines thespring force that can be applied during a dose administration step andtherefore the reduction of the user force needed to administer the dose.As described in greater detail herein, one end of the spring may befixed on the mid-body and the other end of the spring may be fixed to aseparate bearing surface component affixed to the lead screw bearing.

When the user presses the dose knob to inject the selected dose of themedicament contained within the pen, the pre-loaded spring is releasedand the stored force in the spring supports or assists the injection bydriving the lead screw in a distal direction. As such, in thisarrangement, the user needs less force to perform the injection thanwith the device without a spring.

The pen type delivery device drug including the above described designimprovement includes a housing and a lead screw having a longitudinalaxis, a distal end, a proximal end and a threaded shaft. The lead screwis rotatably fixed during dose setting and injecting and only movesaxially in a distal direction relative to the housing during doseadministration. The lead screw may include a bearing foot connected tothe distal end. The lead screw may have a smooth keyway positionedparallel to the longitudinal axis. In one embodiment, the lead screw isalways prevented from moving proximally. The device also has a fluidcontainer or cartridge defining a medicine-filled reservoir with amovable piston at one end and an outlet at the other end, where thepiston is engaged by a bearing connected to the distal end of the leadscrew. The piston is advanced toward the outlet or distal end of thecartridge when the lead screw is moved distally during doseadministration. The piston may be engageable by the lead screw bearingto be advanced toward said outlet when the lead screw is moved distally.

A drive nut is threadedly engaged with the threads on the lead screw andcan rotate and move proximally relative to the lead screw and housingduring dose setting. In other words, the drive nut is threadedly engagedand screwable along the lead screw threaded shaft. A number sleeve isthreadedly engaged with the housing to be screwable relative to thehousing. The number sleeve is screwed outwardly in the proximaldirection relative to the housing during dose setting. A mid-body isaxially fixed inside of the housing, the mid-body comprising tabs thatslidably fit within the keyway in the lead screw to prevent rotation ofthe lead screw within the housing. A preloaded spring is provided thatassists a user of the device during a dose administration step.

A dial link may be connected with the drive nut and axially movable androtatably fixed relative to the drive nut, the dial link being rotatablyfixed with the number sleeve when the dial link and the number sleeveare in a first axial arrangement. The number sleeve is rotatablerelative to the dial link when the dial link and the number sleeve arein a second axial arrangement. In one embodiment, the dial link isslidably and rotationally engaged with the drive nut and is axiallymovable and rotatably fixed relative to the drive nut. The dial link isrotatably fixed with the number sleeve through a clutch when the diallink and number sleeve are in a first axial arrangement and when in asecond axial position the clutch, and hence the number sleeve, aredisengaged from the dial link and the dial link becomes rotatablerelative to the number sleeve. An inner sleeve is threadedly engagedwith the number sleeve, were the inner sleeve is axially movable butrotatably fixed relative to the housing. The inner sleeve is axiallymovable and rotatably fixed relative to the mid-body, e.g. by at leastone lug of the mid-body that slidably fits within at least one slotformed in the inner sleeve.

In one embodiment, the mid-body further comprises at least one metalratchet arm configured to prevent the lead screw from moving in theproximal direction.

In one embodiment, the threading of the number sleeve to the housing isof a first lead, the threading of the inner sleeve to the number sleeveis of a second lead, and the threading of the lead screw threaded shaftis of a third lead, and the first lead, the second lead and the thirdlead are not equal.

During dose setting, the dial link and the number sleeve are in thefirst axial arrangement, whereby a screwing motion of the dial link andthe number sleeve relative to the housing screws the dial link and thenumber sleeve a first axial distance from a home position. The screwingmotion may be caused by a screwing motion of the dose knob that isconnected to the dial link and the number sleeve relative to thehousing. The screwing motion of the dose knob screws the dial link andthe number sleeve a first axial distance from a home position causingthe number sleeve to extend in the proximal direction outwardly from thehousing or body of the device. The screwing motion of the dial linkscrews the drive nut along the lead screw threaded shaft a second axialdistance different than the first axial distance.

During dose dispensing, the dial link and the number sleeve element arein the second axial arrangement, whereby a screwing motion of the numbersleeve relative to the housing back or inward toward the home positionadvances the inner sleeve without rotation in the distal direction toaxially advance the drive nut and thereby the lead screw and themoveable fluid container piston to dispense medicine or fluid from thecartridge outlet. The drive nut is axially fixed to the inner sleeve.

The pen injector disclosed herein can be provided with a mechanicaladvantage that makes it easier for the user to push the dose knob duringthe dispensing of medication, which mechanical advantage can be veryhigh and conveniently selected by the manufacturer during apparatusdesign. This mechanical advantage allows the number sleeve to travel agreater axial distance than the lead screw it advances, thus allowingfor small doses to be delivered.

These as well as other advantages of the various aspects of our improveddrug delivery device, and the manner of attaining them, will becomeapparent to those of ordinary skill in the art by reading the followingdetailed description, with appropriate reference to the accompanyingdrawings.

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments are described herein with reference to thedrawings, in which:

FIG. 1 is an illustration of one embodiment of the present inventionshowing the assembled pen type medication dispensing apparatus where thecap has been removed to reveal the cartridge container affixed to thedose setting mechanism;

FIG. 2 is a close up view of the cartridge container and the pen needlethat is attached to the cartridge container for injection of themedicament;

FIG. 3 is an exploded view of the embodiment from FIG. 1 showing each ofthe individual parts arranged relative to each other as they exist inthe fully assembled device;

FIG. 4 is a perspective view of one embodiment of a spring assisted pendevice in a ready to dial position comprising a preloaded spring;

FIG. 5 is a perspective view of the embodiment in FIG. 4 in a dispensedposition;

FIG. 6 is a close up view of a distal end of the spring of the springassist pen device illustrated in FIG. 4;

FIG. 7 is a perspective view of an alternative embodiment of a springassisted pen device in a ready to dial position comprising a preloadedwave spring;

FIG. 8 is a perspective view of the embodiment in FIG. 7 in a dispensedposition; and

FIG. 9 is a close up view of a distal end the spring of the springassisted pen device illustrated in FIG. 4.

Corresponding reference characters indicate corresponding partsthroughout the several views. Although the drawings representembodiments of the present invention, the drawings are not necessarilyto scale, and certain features may be exaggerated or omitted in some ofthe drawings in order to better illustrate and explain the presentinvention.

DETAILED DESCRIPTION

Referring first to FIGS. 1 to 3, there is shown a drug delivery device 1as an injector pen, which pen has an elongated, substantially writinginstrument-like form, although other forms are within the scope of theinvention. In other words, the drug delivery device 1 may be a pen-typedevice. The drug delivery device 1 comprises a housing having acartridge holder 2, and a main (exterior) body or housing 4.

The drug delivery device 1 and the housing have a distal end and aproximal end. The term “distal end” designates that end of the drugdelivery device 1 or a component thereof which is or is to be arrangedclosest to a dispensing end of the drug delivery device 1. The term“proximal end” designates that end of the device 1 or a componentthereof which is or is to be arranged furthest away from the dispensingend of the device 1. The distal end and the proximal end are spacedapart from one another in the direction of an axis. The axis may be thelongitudinal axis or rotational axis of the device 1.

The proximal end of the cartridge holder 2 and the distal end of themain housing 4 are secured together by appropriate retaining featuresdepending on whether the pen injector is designed as a reusable deviceor as a disposable device. In the latter case, the retaining featurewould be permanent using the connection means described below. If thedevice is reusable, the retaining meaning would be a screw-typeconnection, a Luerlok, snap fit, bayonet, or the like type orcombination of fittings that allow the user to easily disassemble thedevice to replace the empty cartridge with a fresh new cartridge. Inthis illustrated arrangement, the cartridge holder 2 is secured withinthe proximal end of the main body 4.

A cartridge 8 from which a number of doses of a medicinal product may bedispensed is provided in the cartridge holder 2. Preferably, thecartridge 8 contains a type of medicament that must be administeredoften, such as once or more times a day. One such medicament is insulin.A piston 10 is initially retained in the proximal end of the cartridge 8and as each injection is completed gradually moves distally to the emptycartridge position shown in FIG. 2. A removable cap 14 is releasablyretained connected to the main body 4 covering the cartridge holder 2.

The dose setting mechanism of the drug delivery device illustrated inFIGS. 1-3 may be utilized as either for a disposable or reusable drugdelivery device. Where the drug delivery device 1 comprises a disposabledrug delivery device, the cartridge 8 cannot be removed from the drugdelivery device 1 without destroying the device 1. In a disposabledevice, the proximal end of the cartridge holder 2 can be fixedlymounted or secured, via adhesives, ultrasonic welding or in anothersuitable manner, to the dose setting mechanism housing when the injectorpen is assembled by the manufacturer. Alternatively, where the drugdelivery device 1 comprises a reusable drug delivery device, thecartridge 8 is removable and may be removed from the drug deliverydevice 1 without destroying the device 1. In the drug delivery device 1illustrated in FIGS. 1-3, the device is illustrated as a disposable drugdelivery device 1. However, those of ordinary skill in the art willrecognize that the dose setting mechanism could also be used on reusabledrug delivery devices as well, while in the case of a reusable pen,wherein the cartridge holder 2 may be reusable, such that the proximalend can be removably mounted or secured, for example via a threaded,bayonet, or snap fit connection, to a reusable dose setting mechanismhaving a resettable lead screw.

The previously mentioned removable or replaceable cap 14 is used tocover the cartridge holder 2 extending from the main housing 4.Preferably, the outer dimensions of the replaceable cap 14 are similarto or identical to the outer dimensions of the main housing 4 so as toprovide an impression of a unitary whole part when the replaceable cap14 is in position covering the cartridge holder 2. In use, the removablecap 14 is removed and a pen needle assembly 16 comprising a double-endedneedle mounted in a hub may be screwed or pushed onto the distal end ofthe cartridge holder 2 or alternatively may be snapped onto this distalend.

The cartridge 8 is of conventional design and defines a medicine-filledreservoir that is closed at its proximal end by a piston 10 that isaxially slidably and sealably engaged with the cartridge interior wallto hold the fluid medication within the reservoir. The distal, outletend of the cartridge reservoir is sealed by a septum 11 held by a cap 13that is secured to a stepped-down diameter neck portion 15 of thecartridge 8. When the pen needle assembly 16 is mounted on the distalend of the cartridge holder 2, the proximal point of the injectionneedle passes through a central opening in the distal end of thecartridge holder 2, an opening in the cap 13, and penetrates thecartridge septum 11 to provide a fluid flow outlet by which medicinewithin the cartridge reservoir can be dispensed from the distal needletip during operations of injector pen 1. The fluid medicine cartridge 8shown and described above is illustrative and not intended to belimiting as other constructions may be employed within the scope of thisinvention.

A main body 4 of the injector pen 1 houses an axially advanceable leadscrew 22, a drive nut 23, an inner sleeve 29, a dial link 25, a numbersleeve 24, a clutch 26, and a compression spring 27. A dose knob 28 isconnected to the dial link 25 and is used to set the dose and then toinject the set dose. The housing or main body 4 is formed from alightweight material, such as injection molded plastic. The housing 4may be molded as a single, tubular piece for robustness. A window 51 inthe housing 4 near its proximal end can be filled with a magnifying lensthat snaps fits to the housing 4 and allows dosage indicating markings(not shown) on the number sleeve 24 to be readily visible during use.

Near the interior distal end of the housing 4 is mounted a mid-body 20that is formed with a central opening having an inward facinganti-rotation mechanism formed from a pair of diametrically opposedelements or tabs 31 having squared off inward ends that each slidablyfit within longitudinal keyways 32 in the lead screw 22. In alternateembodiments, features other than tabs 31 and keyways, for instance alead screw with flats that fits within a complementarily shaped hole inthe collar, may be used to prevent rotation. The tabs 31 prevent thelead screw 22 from rotating within the housing 4 during pen use, butpermit the lead screw 22 to be shifted longitudinally, such as in thedistal direction toward the cartridge 8. A snap fit or sonic weldingconnection of the mid-body 20 to the tubular housing 4 can be used toprevent axial and rotational relative motion of the mid-body 20 to thehousing 4.

The lead screw 22 is in the form of a screw that is axially translatableand rotatably fixed during dosing and injecting. The term “rotatablyfixed” shall mean in this context that the lead screw 22 is preventedfrom rotation during dosing and injecting. The lead screw 22 includes ashaft with a helical threading 33 along its length, which threading 33is interrupted by longitudinally extending keyways or grooves 32. Athread stop 34 shown at the proximal end of the threading 33 is providedand is used in preventing the pen 1 from being set by a user to delivera dose of medicine larger than remains in cartridge 2. Other forms ofstopping the screw motion may be substituted within the scope of theinvention, for example, the threading 33 at the proximal screw end couldstop near the proximal end where it cannot be cammed in, and such solidscrew with thread stop better ensures the nut 23 will not be torqued offthe screw during dose setting. The distal end of the lead screw 22includes an enlarged, disc-shaped foot or bearing 21 to distributeloading on the cartridge piston 10 that the bearing 21 contacts andthereby directly engages during piston advancing. The separate bearingfoot 21 can be attached, such as with a snap fit 20 that may permitrelative rotation, to the lead screw 22. The lead screw 22 is shown asbeing a one-piece plastic injection molding, but alternate materials ofconstruction and multiple pieces are possible.

The drive nut 23 includes a cylindrical, tube-shaped body with flexiblefingers 36 and clicker teeth 35. The distal region of the drive nut 23is formed with an internal threading 37 that threadedly engages in afriction locking fashion the threading 33 on the lead screw 22. Thethreadings 33 and 37 are shown as a double start threading but may bedifferently formed while still providing suitable friction lockingcapabilities, such as a single start threading or another multiple startthreading. The drive nut 23 is located within the inner sleeve 29 and isaxially, but not rotationally fixed, to the inner sleeve 29. As thedrive nut 23 is rotated relative to the inner sleeve 29 during dosesetting, the clicker teeth 35 engage in a ratchet fashion flexible arms38 that project radially on the inside of the inner sleeve 29. As thedrive nut 23 rotates, the flexible arms 38 ride over the teeth 35creating an audible clicking noise. The teeth 35 are configured so thateach click is equal to one dose volume being set. As few as one flexibleclicker arm 38 may be provided, but the use of four equally angularlyspaced arms 38 aids in centering the drive nut 23 within the innersleeve 29. The hollow interior of the drive nut body 23 locatedproximally of the threading 37 allows free passage of the proximal endof the lead screw 22. The exterior surface of the drive nut 23 isdesigned to cooperatively engage with the dial link 25 so that the diallink 25 is axially free and rotatably fixed relative to the drive nut23. Thus, during use the dial link 25 is axially moveable relative to,but rotatably locked with, the threaded drive nut 23. This connection ispossible because of the cooperation of the proximally extending fingers36 on the drive nut 23 and the distally extending fingers 43 of the diallink 25. These two sets of fingers 36, 43 move axially relative to eachother but engage each other rotationally during dose setting when thedial link 25 is rotated by turning the dose knob 28, which is fixed tothe dial link 25. The drive nut 23 is shown as being a one-piece plasticinjection molding, but other constructions are within the scope of theinvention.

In the shown embodiment, the dial link 25 is formed in one piece of aninjection molded plastic and which fits within the body 4. A flange 40that rings a central region of the dial link body includes splines orteeth 39 that extend from the distal face of the flange 40, and teeth 41that extend from the proximal face of the flange 40. A stepped-downportion of the proximal end of the dial link 25 forms an axially andproximally extending stem 42. The distal end of the dial link bodyincludes a pair of fingers 43 that fit with fingers 36 of the drive nut23 to allow axial motion but not rotational motion of the drive nut 23relative to the dial link 25, thereby rotationally locking the piecestogether within the same annular space. The fingers 36 and 43 extendsufficiently axially to ensure that they do not disengage during thesetting of the maximum pen dose for injection.

An injection molded plastic dose knob 28 with a proximal face, andhaving a distally facing and centrally located bearing collar andalignment post 55 is provided. The stem 42 of the of the dial link 25receives the dose knob alignment post and can be ultrasonically weldedwithin the bearing collar during manufacturing assembly, so as toaxially and rotatably fix together the dose knob 28 and the dial link25. The term “rotatably fix” shall mean in this context that anyrelative rotational movement between the dose knob 28 and the dial link25 is prevented. A dose knob skirt 50 distally extends from the radialperiphery of the dose knob distal face to serve as a grip portion for auser during dose setting.

Coaxially mounted around the dial link 25 is the number sleeve 24. Thenumber sleeve 24 has a cylindrical exterior surface 30 with a threading52 formed as a helical groove that engages a corresponding threading 62formed on the interior surface of body 4 to threadedly engage the numbersleeve 24 to the pen housing 4. Threadings 52 and 62 are shown as asingle start threading but may be differently formed. The threading 62abuts the end 63 of the threading 52 on the number sleeve 24 at themaximum pen dose, assuming the cartridge 8 is sufficiently full for sucha maximum dose. A stop surface 64 on the distal end of the outer surfaceof the number sleeve 24 is positioned in slightly spaced apartrelationship with a projecting stop at the zero dose position, andanother stop surface is to be abutted by the stop if a user attempts tomanually screw the screw element below a zero dose position. A hollowinterior 65 of the number sleeve 24 is defined by a cylindrical interiorsurface provided with a helical threading 67.

The outside diameter of the number sleeve 24 is selected such that itcan fit inside the dose knob 28. The proximal end region of the numbersleeve 24 includes a number of notches 70 and corresponding windows 71that are alternately spaced around the circumference. The number sleeve24 includes around its exterior surface 30 suitable indicia oftherapeutic dose size as visible through body 4 opening 51. A clutch 26fits within the open proximal end of the number sleeve 24. Ears 72 onthe clutch 26 fit within notches 70 and assembly fingers 73 snap lockinto the windows 71 to axially and rotatably lock the number sleeve 24and the clutch 26 together during manufacturing assembly. A ring ofaxially extending teeth 54 on the clutch 26 formed in the interiorsurface of flange cooperate with the dial link teeth 41 proximallyfacing on the dial link 25. Disposed between the clutch 26 and theinside portion of the dose knob 28 is the compression or biasing spring27 that urges the clutch 26 to engage the teeth 41 on the dial link 25.During injection, when a user manually applies a plunging force ontoproximal face of the dose knob 28, the spring 27 is elasticallycompressed, thus disengaging the clutch 26 and the number sleeve 24 fromthe dial link 25. The flange teeth 41 on the dial link 25 and clutchteeth 54 mesh when the spring 27 has biased the clutch 26 and theattached number sleeve 24 to the dose knob 28 and the dial link 25. Thedose knob 28 and the dial link 25 are not meshed with the clutch 26 andthe number sleeve 24 when the spring 27 has been sufficiently compressedduring injecting. While a helically coiled metal wire spring 27 isshown, other forms of commonly known biasing elements may besubstituted.

The inner sleeve 29 is injection molded from plastic and includes atubular body that fits into the hollow 65 of the number sleeve 24. Theinner sleeve 29 has a helical threading 75 on its outer surface thatengages the internal threading 67 on the inside surface of the numbersleeve 24. The threadings 67 and 75 are shown as a single startthreading, but may be differently formed. The proximal most portion ofthe end of inner sleeve 24, which end is partially helically shapedcorresponding to the threading, is notched to form a partial ring ofaxially projecting teeth 76 that, when meshed with dial link distallyfacing teeth 39, serve to rotatably lock together the dial link 25 andthe inner sleeve 29. The inner sleeve 29 is keyed to the pen body 4through the intermediate mid-body 20 that is axially and rotationallyfixed to the body 4. The distal end of the inner sleeve 29 has a pair ofridge-defined slots 77 on the periphery of the inner sleeve 29 whichaxially, slidably receive the lugs 78 radially inwardly projecting fromthe mid-body 20.

Openings molded into the inner sleeve 29 define four resilient fingers38 having radially inwardly projecting teeth that are axially orientedand shaped to project into a recess in the distal end of the drive nut23 that has radially projecting teeth or ridges 35 such that theinwardly projecting teeth click over, in either rotational direction,teeth 35 during dose setting. The fingers 38 with teeth cooperate withthe recess on the drive nut 23 to hinder the nut 23 from coming off theinner sleeve 29 after being assembled thereto during manufacture.

To facilitate back-driving during dose delivery, the threadedconnections of the number sleeve 24 and the body 4, and the numbersleeve 24 and the inner sleeve 29, are non-binding and provided byprojecting 60° face angle threads that slide within correspondinglydesigned recessed grooves. With these threadings, it is preferred thatthe mechanical advantage is 3.4 or greater, and the screw lead of thedrive member or drive nut 23 is 0.108 inch.

The operation of the above described embodiment will now be explained.The pen 1 with a needle 16 attached should first be primed to remove anytrap air in the cartridge 8 and to ensure the bearing 21 is in contactwith the proximal end of the cartridge stopper or piston 10. Inparticular, typically while clutching the pen body 4 in one hand, a usermanually grips the dose knob skirt 50 and then begins to turn the doseknob 28 relative to the body 4. At the zero dose arrangement, and aslong as the dose knob 28 is not also being plunged which is improper,the dose knob 28 can only be rotated in a dose increasing direction dueto the number sleeve 24 not being further movable distally. A user stopsthe rotating after a short amount of number sleeve travel that isassociated with a small delivery volume, such as one or two units, whichis indicated by the markings visible through the window 51. Then, andafter removing the cap 14 and any other needle cap present, and whilepointing the needle tip upward, the user applies a plunging force on thedose knob 28 to drive it distally until the number sleeve 24 returns tothe zero dose position, at which the number sleeve threading 52 hasreached the distal end of the body threading 62, during which plungingaction the piston 10 is shifted forward within the cartridge 8. If auser sees that the piston movement has caused liquid to reach the needledistal tip, the priming process is complete. If no liquid is visible atthe needle tip, the priming steps are repeated as needed. After priming,the pen 1 is ready to be used for an actual injection.

First, a user prepares the pen by setting the desired dose, as visiblein the window 51, by turning of the dose knob 28. If the user dials uptoo large of a dose, and without expelling any medicine, the user canrotate down the dial by turning the dose knob 28 in the oppositedirection, all the way back to zero if desired. To set a dose, the doeknob 28 is turned in a clockwise direction. Because the dose knob 28 andthe dial link 25 are fixed rotationally, the dial link 25 is rotatedcausing the distally facing fingers 43 to engage the proximally facingfingers 36 of the drive nut 23 to thereby turn the drive nut in samedirection. Rotation of the drive nut 23 causes the nut 23 to rotaterelative to the stationary lead screw 22 whereby the nut 23 moves orclimbs up the lead screw 22 in the proximal direction. The drive nut 23rotates relative to the inner sleeve 29 that is held rotationally fixedrelative to the body 4 through the splined connection to the mid-body20. Because the drive nut 23 and the inner sleeve 29 are axially fixed,proximal axial movement of the drive nut 23 causes the inner sleeve 29to slide proximally relative to the mid-body 20. Because the clutch 26is rotationally fixed with the dial link 25, the clutch 26 rotatescausing the number sleeve 24 to rotate and to spin out proximally awayfrom body 4. Because the pitch of the threads on the number sleeve 24are greater than the pitch of the threads on the inner sleeve 29, thenumber sleeve 24 and the dial link 25 will translate a larger axiallydistance compared to the inner sleeve 29 and the drive nut 23.

To inject the dose, after pen 1 is manipulated so the injection needledistal tip properly penetrates, for example, a user's skin, an axial,distal plunging force is applied to the knob face 53 to force the diallink 25 axially in the distal direction toward the body 4, such as witha thumb or index finger of the hand which grasps the housing 4.Initially during injecting, the dial link 25 is shifted axially, whichshifting motion compresses the biasing spring 27 to close the gapbetween the knob surface and the proximal end of the number sleeve 24.The biasing spring 27 is designed to compress prior to the number sleeve24 moving relative to the body 4. When the dial link 25 shifts relativeto the number sleeve 24 to the axial arrangement of the drive nut 23,the clutch teeth 54 and the dial link teeth 42 disengage to allow abackwards rotation of the number sleeve 24 relative to the dial link 25.During the axial movement of the dial link 25, the drive nut 23 does notmove axially or rotationally. When the number sleeve 24 and the clutch26 rotatably uncouple from the dial link 25, as the dial link 25 iscontinued to be axially plunged without rotation by the user by theplunging of the dose knob 28, the number sleeve 24 screws into the body4 as it spins relative to the dose knob 28 and the dose markings on thenumber sleeve 24 that indicate the amount still remaining to be injectedare visible through the window 51.

As it screws down, the number sleeve 24 causes the inner sleeve 29 to inessence screw up the internal thread inside of the number sleevethreading as the inner sleeve 29 advances distally a lesser distancethan the number sleeve 24. The advancement of the inner sleeve 29, dueto the abutting or direct engagement with the distal end of the drivenut 23, advances the drive nut 23 without rotation, which due to itsthreaded connection with the lead screw 22 advances the lead screw 22axially without rotation, which lead screw advancement shifts thecartridge piston 10 to expel medication from the cartridge reservoir.The injection is completed when the number sleeve threading 52 hasreached the distal end of the body 4, at which time the pen 1 is onceagain arranged in the ready state or zero dose position.

The pen 1 can continue to be used to deliver any desired dose until themedicine remaining in the cartridge 8 is insufficient for a properdosing. This insufficiency is indicated to the user by the inability tofully set the desired dose due to drive nut threading 37 abutting thethread stop 34 on the lead screw 22, at which time the drive nut 23 andthe dial link 25 cannot be rotated proximally any farther. Wheninsufficient medicine remains, the pen 1 is to be disposed of andreplaced with a similar but entirely new pen.

As discussed above, one perceived problem of this commercial injectiondevice is that it is entirely manually activated. That is, thiscommercial medication delivery pen may be termed a manual pen since theinjection of a medicament contained within the pen is delivered by aforce that is purely provided by the user of the pen. As such, theinjection of a medicament is not assisted by any type of spring element.One disadvantage of such a purely manually driven pen is that the userwill be called upon to apply a force to withdraw the dose setting membera certain axially fixed distance and then press upon the dose settingmember to perform the injection. This may be a difficult manualprocedure, especially for persons having reduced motor skills or reducedfinger strength, such as a child, elderly people, disabled people; orthose suffering from diabetes. To solve this problem, the presentinvention modifies the original design of the dosing mechanism so as toprovide a spring assisted feature during a dose administration step.

For example, FIG. 4 is a perspective view of one embodiment of a springassist pen device 80 in a ready to dial position. As illustrated, thisspring assisted pen device 80 comprises a tensioned or pre-loaded spring82 that is positioned between a distal end of the mid body 20 and aseparate bearing surface component 81 that is affixed to the bearing 21of the lead screw 22.

For example, FIG. 6 illustrates a close up view of the distal end 84 ofthe spring 82 and how it cooperates with the bearing 21 of the leadscrew 22. As illustrated, the bearing 21 further comprises the separatebearing surface component 81 that defines a recess 83. It is within thisrecess 83 that the distal end 84 of the spring 82 is situated. In thisconfiguration, the bearing surface component 81 is constructed to absorbthe rotational force of the spring 82. The bearing surface component 81is fixedly attached to a proximal surface 85 of the bearing 21 of thelead screw 22. Returning to FIG. 4, a proximal end 86 of the tensionspring 82 is fixedly attached to the mid-body 20.

As described above, to set a dose with this first spring assistembodiment, the dose knob 28 is turned in a clockwise direction. Becausethe dose knob 28 and the dial link 25 are fixed rotationally, the diallink 25 is rotated causing the distally facing fingers 43 to engage theproximally facing fingers 36 of the drive nut 23 to thereby turn thedrive nut 23 in the same direction. Rotation of the drive nut 23 causesthe nut 23 to rotate relative to the stationary lead screw 22 wherebythe nut 23 moves or climbs up the lead screw 22 in the proximaldirection. The drive nut 23 rotates relative to the inner sleeve 29 thatis held rotationally fixed relative to the body 4 through the splinedconnection to the mid-body 20. Because the drive nut 23 and the innersleeve 29 are axially fixed, proximal axial movement of the drive nut 23causes the inner sleeve 29 to slide proximally relative to the mid-body20. One advantage of the spring assisted delivery device illustrated inFIG. 4 is that the setting of the dose is not affected by theintroduction of the preloaded spring 82. As such, no additional settingforce is required by the user.

To inject the dose, and similar to the device discussed earlier withrespect to FIGS. 1-3, an axial, distal plunging force is applied to theknob face 53 to force the dial link 25 axially in the distal directiontoward the body 4, such as with a thumb or index finger of the handwhich grasps the housing 4. Initially during injecting, the dial link 25is shifted axially, which shifting motion compresses the biasing spring27 to close the gap between the knob surface and the proximal end of thenumber sleeve 24. The biasing spring 27 is designed to compress prior tothe number sleeve 24 moving relative to the body 4. When the dial link25 shifts relative to the number sleeve 24 to the axial arrangement ofthe drive nut 23, the clutch teeth 54 and the dial link teeth 42disengage to allow a backwards rotation of the number sleeve 24 relativeto the dial link 25. During the axial movement of the dial link 25, thedrive nut 23 does not move axially or rotationally. When the numbersleeve 24 and the clutch 26 rotatably uncouple from the dial link 25, asthe dial link 25 is continued to be axially plunged without rotation bythe user by the plunging of the dose knob 28, the number sleeve 24screws into the body 4 as it spins relative to the dose knob 28 and theinner sleeve 29 moves in the in the distal direction under the assistedforce of the tensioned spring 82. The advancement of the inner sleeve29, due to the abutting or direct engagement with the distal end of thedrive nut 23, advances the drive nut 23 without rotation, which due toits threaded connection with the lead screw 22 advances the lead screw23 axially with the assistance of the tensioned spring 82. Springassisted advancement of the lead screw 22 shifts the cartridge piston 10to expel medication from the cartridge reservoir. The injection iscompleted when the number sleeve threading 52 has reached the distal endof the body 4, at which time pen 1 is once again arranged in the readystate or zero dose position. FIG. 5 is a perspective view of theembodiment in FIG. 4 in a dispensed position.

FIG. 7 is a perspective view of an alternative arrangement of a springassisted pen device 90 in a ready to dial position. As illustrated, thisspring assisted pen device 90 comprises a tensioned or pre-loaded wavespring 92.A wave spring may be a flat wire compression spring, e.g. awavy metal washer. One embodiment may be crest-to-crest wave spring.This spring is pre-stacked in series. One embodiment of a wave spring isthe nested wave spring. Nest springs are pre-stacked in parallel fromone continuous filament of flat wire.

This wave spring 92 is positioned between the mid body 20 and a proximalface of the bearing 21 of the lead screw 22. Specifically, a distal end94 of the compressed or loaded wave spring 92 resides along the proximalface of the bearing 21 of the lead screw 22 and a proximal end 96 of thewave spring 92 is fixedly attached to the mid-body 20. A user sets adose with the spring assist pen device 90 in a similar fashion as how auser sets a dose with the spring assisted pen device 80 illustrated inFIGS. 4-6. Similarly, one advantage of this spring assisted pen device90 is that the setting of the dose is not affected by the introductionof the wave spring 92, meaning that no additional setting force isintroduced during the dose setting procedure.

Once a dose has been set, when the user presses the dose knob 28 toinject the selected dose of the medicament contained within the pen 90,the wave spring 92 is released and the stored force in the wave spring92 assists with distally advancing or driving the lead screw 22 duringthis injection step. As such, in this arrangement, the user needs lessforce to perform the injection than with the device without a spring.FIG. 8 is a perspective view of the embodiment in FIG. 7 in a dispensedposition with the wave spring 92 in an extended position.

FIG. 9 illustrates a close up view of a distal end 94 of the wave spring92. As illustrated, the distal end 94 of the wave spring 92 residesdirectly on a proximal face 95 of the bearing 21. In contrast to thecompressed spring 80 and bearing 21 configuration illustrated in FIG. 6,the wave spring assisted pen drug delivery device 90 does not require aseparate bearing surface component affixed to the bearing 21 since thereis no need to absorb any type of rotational force with the wave spring92.

The terms “medicament” or “medicinal product”, as used herein, mean apharmaceutical formulation containing at least one pharmaceuticallyactive compound,

wherein in one embodiment the pharmaceutically active compound has amolecular weight up to 1500 Da and/or is a peptide, a protein, apolysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or afragment thereof, a hormone or an oligonucleotide, or a mixture of theabove-mentioned pharmaceutically active compound,

wherein in a further embodiment the pharmaceutically active compound isuseful for the treatment and/or prophylaxis of diabetes mellitus orcomplications associated with diabetes mellitus such as diabeticretinopathy, thromboembolism disorders such as deep vein or pulmonarythromboembolism, acute coronary syndrome (ACS), angina, myocardialinfarction, cancer, macular degeneration, inflammation, hay fever,atherosclerosis and/or rheumatoid arthritis,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one peptide for the treatment and/or prophylaxis ofdiabetes mellitus or complications associated with diabetes mellitussuch as diabetic retinopathy,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one human insulin or a human insulin analogue orderivative, glucagon-like peptide (GLP-1) or an analogue or derivativethereof, or exendin-3 or exendin-4 or an analogue or derivative ofexendin-3 or exendin-4.

Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) humaninsulin; Asp(B28) human insulin; human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N—(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N—(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyheptadecanoyl) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the sequenceH-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

Exendin-4 derivatives are for example selected from the following listof compounds:

H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,

H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,

des Pro36 Exendin-4(1-39),

des Pro36 [Asp28] Exendin-4(1-39),

des Pro36 [IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or

des Pro36 [Asp28] Exendin-4(1-39),

des Pro36 [IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),

wherein the group -Lys6-NH2 may be bound to the C-terminus of theExendin-4 derivative;

or an Exendin-4 derivative of the sequence

des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),

H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,

des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,

H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,

H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2, H-(Lys)6-des Pro36 [Met(O)14, Asp28]Exendin-4(1-39)-Lys6-NH2,

des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,

H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,

H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]Exendin-4(1-39)-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(S1-39)-(Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2;

or a pharmaceutically acceptable salt or solvate of any one of theafore-mentioned Exendin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists as listed in RoteListe, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin,Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid,a heparin, a low molecular weight heparin or an ultra-low molecularweight heparin or a derivative thereof, or a sulphated, e.g. apoly-sulphated form of the above-mentioned polysaccharides, and/or apharmaceutically acceptable salt thereof. An example of apharmaceutically acceptable salt of a poly-sulphated low molecularweight heparin is enoxaparin sodium.

Antibodies are globular plasma proteins (˜150 kDa) that are also knownas immunoglobulins which share a basic structure. As they have sugarchains added to amino acid residues, they are glycoproteins. The basicfunctional unit of each antibody is an immunoglobulin (Ig) monomer(containing only one Ig unit); secreted antibodies can also be dimericwith two Ig units as with IgA, tetrameric with four Ig units liketeleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

The Ig monomer is a “Y”-shaped molecule that consists of fourpolypeptide chains; two identical heavy chains and two identical lightchains connected by disulfide bonds between cysteine residues. Eachheavy chain is about 440 amino acids long; each light chain is about 220amino acids long. Heavy and light chains each contain intrachaindisulfide bonds which stabilize their folding. Each chain is composed ofstructural domains called Ig domains. These domains contain about 70-110amino acids and are classified into different categories (for example,variable or V, and constant or C) according to their size and function.They have a characteristic immunoglobulin fold in which two β sheetscreate a “sandwich” shape, held together by interactions betweenconserved cysteines and other charged amino acids.

There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ,and μ. The type of heavy chain present defines the isotype of antibody;these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies,respectively.

Distinct heavy chains differ in size and composition; α and γ containapproximately 450 amino acids and δ approximately 500 amino acids, whileμ and ε have approximately 550 amino acids. Each heavy chain has tworegions, the constant region (CH) and the variable region (VH). In onespecies, the constant region is essentially identical in all antibodiesof the same isotype, but differs in antibodies of different isotypes.Heavy chains γ, α and δ have a constant region composed of three tandemIg domains, and a hinge region for added flexibility; heavy chains μ andε have a constant region composed of four immunoglobulin domains. Thevariable region of the heavy chain differs in antibodies produced bydifferent B cells, but is the same for all antibodies produced by asingle B cell or B cell clone. The variable region of each heavy chainis approximately 110 amino acids long and is composed of a single Igdomain.

In mammals, there are two types of immunoglobulin light chain denoted byλ, and κ. A light chain has two successive domains: one constant domain(CL) and one variable domain (VL). The approximate length of a lightchain is 211 to 217 amino acids. Each antibody contains two light chainsthat are always identical; only one type of light chain, κ or λ, ispresent per antibody in mammals.

Although the general structure of all antibodies is very similar, theunique property of a given antibody is determined by the variable (V)regions, as detailed above. More specifically, variable loops, threeeach the light (VL) and three on the heavy (VH) chain, are responsiblefor binding to the antigen, i.e. for its antigen specificity. Theseloops are referred to as the Complementarity Determining Regions (CDRs).Because CDRs from both VH and VL domains contribute to theantigen-binding site, it is the combination of the heavy and the lightchains, and not either alone, that determines the final antigenspecificity.

An “antibody fragment” contains at least one antigen binding fragment asdefined above, and exhibits essentially the same function andspecificity as the complete antibody of which the fragment is derivedfrom. Limited proteolytic digestion with papain cleaves the Ig prototypeinto three fragments. Two identical amino terminal fragments, eachcontaining one entire L chain and about half an H chain, are the antigenbinding fragments (Fab). The third fragment, similar in size butcontaining the carboxyl terminal half of both heavy chains with theirinterchain disulfide bond, is the crystalizable fragment (Fc). The Fccontains carbohydrates, complement-binding, and FcR-binding sites.Limited pepsin digestion yields a single F(ab′)2 fragment containingboth Fab pieces and the hinge region, including the H—H interchaindisulfide bond. F(ab′)2 is divalent for antigen binding. The disulfidebond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, thevariable regions of the heavy and light chains can be fused together toform a single chain variable fragment (scFv).

Pharmaceutically acceptable salts are for example acid addition saltsand basic salts. Acid addition salts are e.g. HCl or HBr salts. Basicsalts are e.g. salts having a cation selected from alkali or alkaline,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4), whereinR1 to R4 independently of each other mean: hydrogen, an optionallysubstituted C1-C6-alkyl group, an optionally substituted C2-C6-alkenylgroup, an optionally substituted C6-C10-aryl group, or an optionallysubstituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are described in “Remington'sPharmaceutical Sciences” 17.ed. Alfonso R. Gennaro (Ed.), MarkPublishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia ofPharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates

While this invention has been shown and described as having variousdesigns, the present invention may be modified within the spirit andscope of this disclosure. For example, to deliver a fixed dose, the pen1, 80, 90 would preferably be modified such that the maximum that thedial could be screwed out to prepare the pen 1, 80, 90 for injectionwould correspond to the fixed dose. Such a fixed dose pen couldeliminate numerical dosage indicating marking, and instead provide usercues in the form of, for example, instructions and a graphical dosingindicator. This disclosure is therefore intended to cover anyvariations, uses or adaptations of the invention using its generalprinciples. Further, this disclosure is intended to cover suchdepartures from the present disclosure as come within known or customarypractice in the art to which this invention pertains.

1-15. (canceled)
 16. A spring assisted drug delivery device comprising:a housing; a piston rod having a longitudinal axis, a distal end and aproximal end that is axially movable in a distal direction relative tothe housing, a mid-body fixed inside of the housing and coupled to thepiston rod in such a manner that the piston rod is axially movable inthe distal direction relative to the mid-body, and wherein a preloadedspring is operatively coupled to the piston rod in such a manner thatthe spring is released and the stored force in the spring supportsdriving the piston rod in the distal direction during a doseadministration step.
 17. The spring assisted drug delivery device ofclaim 16 wherein the preloaded spring is operatively coupled between themid-body and the piston rod or between the housing and the piston rod.18. The spring assisted drug delivery device of claim 17 wherein thepreloaded spring is operatively coupled between the mid-body and abearing of the piston rod.
 19. The spring assisted drug delivery deviceof claim 18 wherein the preloaded spring is operatively coupled to aseparate bearing surface component affixed to a proximal surface of thebearing.
 20. The spring assisted drug delivery device of any of claim 16wherein the preloaded spring comprises a wave spring.
 21. The springassisted drug delivery device of claim 20 wherein the wave spring isoperatively coupled to a proximal surface of the bearing.
 22. The springassisted drug delivery device of claim 16 wherein the piston rodincludes a threaded shaft and a bearing connected to the distal end. 23.The spring assisted drug delivery device of claim 22 wherein the pistonrod is rotatably fixed during dose setting and dose delivery, and themid-body is designed to prevent rotation of the piston rod within thehousing.
 24. The spring assisted drug delivery device of claim 23further comprising: a drive nut threadedly engaged and screwable alongthe piston rod; a number sleeve threadedly engaged with the housing tobe screwable relative to the housing; wherein a dial link is connectedwith the drive nut and axially movable and rotatably fixed relative tothe drive nut, the dial link being rotatably fixed with the numbersleeve when the dial link and the number sleeve are in a first axialarrangement, the number sleeve being rotatable relative to the dial linkwhen the dial link and the number sleeve are in a second axialarrangement.
 25. The spring assisted drug delivery device of claim 24wherein an inner sleeve is threadedly engaged with the number sleeve,the inner sleeve being axially movable and rotatably fixed relative tothe housing.
 26. The spring assisted drug delivery device of claim 25wherein the inner sleeve is axially movable and rotatably fixed relativeto the mid-body.
 27. The spring assisted drug delivery device of claim16, wherein the piston rod has a keyway positioned parallel to thelongitudinal axis; the mid-body comprising tabs that slidably fit withinthe keyway.
 28. The spring assisted drug delivery device of claim 16,wherein the mid-body further comprises at least one ratchet armconfigured to prevent the piston rod from moving in the proximaldirection.
 29. The spring assisted drug delivery device of claim 24,wherein the threading of the number sleeve to the housing is of a firstlead, the threading of the inner sleeve to the number sleeve is of asecond lead, and the threading of the piston rod threaded shaft is of athird lead, and the first lead, the second lead and the third lead arenot equal.
 30. The spring assisted drug delivery device of claim 23,wherein during dose setting, the dial link and the number sleeve are inthe first axial arrangement, whereby a screwing motion of the dial linkand the number sleeve relative to the housing screws the dial link andthe number sleeve a first axial distance from a home position, whichscrewing motion of the dial link screws the drive nut along the pistonrod threaded shaft a second axial distance that is different than thefirst axial distance and wherein during dose delivery, the dial link andthe number sleeve are in the second axial arrangement, whereby ascrewing motion of the number sleeve relative to the housing back towardthe home position advances the inner sleeve without rotation in thedistal direction to axially advance the drive nut that is axially fixedto the inner sleeve and thereby the piston rod and the movable piston todispense fluid from the cartridge outlet.